CN107698550A - A kind of xanthone compound of 2,4 difluorophenyl substitution and its preparation method and application - Google Patents
A kind of xanthone compound of 2,4 difluorophenyl substitution and its preparation method and application Download PDFInfo
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- CN107698550A CN107698550A CN201710884013.3A CN201710884013A CN107698550A CN 107698550 A CN107698550 A CN 107698550A CN 201710884013 A CN201710884013 A CN 201710884013A CN 107698550 A CN107698550 A CN 107698550A
- Authority
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- China
- Prior art keywords
- difluorophenyl
- compound
- dihydroxy
- preparation
- xanthone
- Prior art date
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- JNELGWHKGNBSMD-UHFFFAOYSA-N xanthone powder Natural products C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- -1 xanthone compound Chemical class 0.000 title claims abstract description 17
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 6
- 102000003425 Tyrosinase Human genes 0.000 claims abstract description 17
- 108060008724 Tyrosinase Proteins 0.000 claims abstract description 17
- 150000007964 xanthones Chemical class 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 230000033228 biological regulation Effects 0.000 claims abstract description 7
- 235000013305 food Nutrition 0.000 claims abstract description 6
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 5
- 239000002537 cosmetic Substances 0.000 claims abstract description 5
- 230000036541 health Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 12
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 11
- 229960001553 phloroglucinol Drugs 0.000 claims description 11
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 7
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 claims description 7
- 229960003019 loprazolam Drugs 0.000 claims description 7
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical class C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 6
- 230000004060 metabolic process Effects 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 230000037429 base substitution Effects 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- GTHOERCJZSJGHB-UHFFFAOYSA-N 1,3-dihydroxyxanthen-9-one Chemical compound C1=CC=C2C(=O)C3=C(O)C=C(O)C=C3OC2=C1 GTHOERCJZSJGHB-UHFFFAOYSA-N 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 8
- 201000007270 liver cancer Diseases 0.000 description 8
- 208000014018 liver neoplasm Diseases 0.000 description 8
- 201000005202 lung cancer Diseases 0.000 description 8
- 208000020816 lung neoplasm Diseases 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 125000004212 difluorophenyl group Chemical group 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 208000000389 T-cell leukemia Diseases 0.000 description 2
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UGEJOEBBMPOJMT-UHFFFAOYSA-N 3-(trifluoromethyl)phenol Chemical class OC1=CC=CC(C(F)(F)F)=C1 UGEJOEBBMPOJMT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q90/00—Cosmetics or similar toiletry preparations for specific uses not provided for in other groups of this subclass
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
A kind of xanthone compound of 2,4 difluorophenyls substitution, is 7 (2,4 difluorophenyl) 1,3 dihydroxy xanthone, its structure is shown below：
Description
Technical field
The present invention relates to biochemical field of medicaments, and in particular to the xanthone chemical combination of 2,4- of one kind difluorophenyls substitution
Thing and its preparation method and application.
Background technology
Xanthone is also referred to as xanthone, is the secondary metabolite separated from some plants and microorganism at first, contains
There is the precursor structure of dibenzo-gamma-pyrone.Such compound has many important bioactivity, such as anti-hypertension,
Anti- depauperation, antibacterial, antithrombotic and antitumor isoreactivity.These different bioactivity are by different in xanthone female ring
Substituent determines.
Different substituents determines its multiple biological activities in xanthone female ring, and one or more substituent changes
Change can all influence its bioactivity.The xanthone compound with certain bioactivity is obtained, it is necessary to first synthesize oxa-
Anthrone compound, related activity screening is then carried out again.
The content of the invention
Therefore, it is an object of the invention to provide a kind of xanthone chemical combination with certain physiology and pharmacological activity
Thing.
To realize the purpose of the present invention, present invention employs following technical scheme：
2,4- of one kind difluorophenyls substitution xanthone compound, the compound be 7- (2,4- difluorophenyl)-
1,3- dihydroxy xanthone, shown in its structure such as chemical formula (I)：
Present invention also offers a kind of preparation method of compound shown in formula I, including by 5- (2,4- difluorophenyl) -2-
The process that hydroxybenzoic acid, phloroglucin, phosphorus pentoxide and Loprazolam are reacted.
Preferably, the mol ratio of 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids and phloroglucin is 1:1.
Preferably, comprise the following steps：
1) phosphorus pentoxide is dissolved in Loprazolam, prepares the first mixed solution；
2) the first mixed solution is added into 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids and phloroglucin, carries out cyclization
Reaction, generation 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthones；
Preferably, it is further comprising the steps of：
2) solution containing 7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthones after the completion of reacting is analysed
Go out, filter, column chromatography for separation, 7- (2,4- difluorophenyl) -1, the 3- dihydroxy xanthones purified.
Preferably, in the step 1), solution temperature is controlled at 105~115 DEG C.
Preferably, in the step 2), reaction temperature control at 88~92 DEG C, reaction time control 18~
22min。
In preparation, the control of temperature is vital.Temperature is too high to make raw material be carbonized and reduce yield, and warm
Degree is too low and can influence the speed of reaction.
Present invention also offers application of the compound shown in formula I in terms of tyrosinase activity is suppressed.
Present invention also offers application of the compound in terms of antineoplastic shown in formula I.
Present invention also offers compound shown in formula I in tyrosinase Metabolism regulation medicine, health products, food, cosmetics
The application of aspect.
Compound 7- (2,4- difluorophenyl) shown in formula I provided by the present invention -1,3- dihydroxy xanthones, it is one
The new xanthone compound of kind, there is obvious antitumor activity and suppress the activity of tyrosinase, resist available for preparing
Tumour medicine and tyrosine Metabolism regulation medicine, health products, food, cosmetics.The preparation side of compound shown in formula I
Method, simple to operate, reaction condition is gentle, yield is high, a large amount of preparations available for compound shown in formula I.
Embodiment
To describe the technology contents of technical scheme, construction feature, the objects and the effects in detail, below in conjunction with specific
Embodiment is explained in detail.
To realize the purpose of the present invention, present invention employs following technical scheme：
2,4- of one kind difluorophenyls substitution xanthone compound, the compound be 7- (2,4- difluorophenyl)-
1,3- dihydroxy xanthone, shown in its structure such as chemical formula (I),
Present invention also offers a kind of preparation method of compound shown in formula I, including by 4- trifluoromethyl -2- hydroxy benzenes
The process that formic acid, phloroglucin, phosphorus pentoxide and Loprazolam are reacted.
Preferably, the mol ratio of 4- trifluoromethyls -2 hydroxybenzoic acid and phloroglucin is 1:1.
Present invention also offers a kind of preparation method of compound shown in formula I, including by 5- (2,4- difluorophenyl) -2-
The process that hydroxybenzoic acid, phloroglucin, phosphorus pentoxide and Loprazolam are reacted.
Preferably, the mol ratio of 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids and phloroglucin is 1:1.
Preferably, comprise the following steps：
1) phosphorus pentoxide is dissolved in Loprazolam, prepares the first mixed solution；
2) the first mixed solution is added into 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids and phloroglucin, carries out cyclization
Reaction, generation 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthones；
Preferably, it is further comprising the steps of：Contain 7- (2,4 difluorobenzene base) -1,3- dihydroxies after the completion of 2) reacting
The solution of base xanthone is separated out, filtered, column chromatography for separation, 7- (2,4- difluorophenyl) -1, the 3- dihydroxies purified
Base xanthone.
Preferably, in the step 1), solution temperature is controlled at 105~115 DEG C.
Preferably, in the step 2), reaction temperature control at 88~92 DEG C, reaction time control 18~
22min。
Present invention also offers application of the compound shown in formula I in terms of tyrosinase activity is suppressed.
Present invention also offers application of the compound in terms of antineoplastic shown in formula I.
Present invention also offers compound shown in formula I in tyrosinase Metabolism regulation medicine, health products, food, cosmetics
The application of aspect.
Compound 7- (2,4- difluorophenyl) shown in formula I provided by the present invention -1,3- dihydroxy xanthones, it is one
New xanthone compound, there is obvious antitumor activity and suppress the activity of tyrosinase, it is anti-swollen available for preparing
Tumor medicine and tyrosine Metabolism regulation medicine.The preparation method of compound shown in formula I, simple to operate, reaction condition temperature
With a large amount of preparations available for compound shown in formula I.
For a further understanding of the present invention, with reference to embodiment, the present invention is described in detail.
Embodiment 1：The synthesis of 7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthones
By 0.68g phosphorus pentoxides (4.8mmol) and 15mL Loprazolams (MeSO3H 50mL round-bottomed flasks) are sequentially added
In, 110 DEG C are heated to, stirring makes its dissolving, and then reaction solution is down to 90 DEG C, sequentially adds 0.40g 5- (2,4- difluorobenzenes
Base) -2 hydroxybenzoic acid (1.6mmol) and 0.20g phloroglucins (1.6mmol), react 20min at 90 DEG C.By reaction solution
It is poured into water, separates out solid, filters, naturally dry, the mixed solvent (V of head product ethyl acetate and petroleum etherEthyl acetate：
VPetroleum ether=1：10) 200-300 mesh pressurized silica gel posts are crossed, obtain 0.41g yellow solids, yield 76.0%.
IR(KBr)vmax809,1078,1103,1175,1283,1300,1320,1343,1422,1485, 1522,
1569,1607,1656,2852,2923,2959,3138,3427cm-1；1H NMR(CD3COCD3, 500MHz)δ6.29(1H,d,
J=2.2Hz, H-2), 6.48 (1H, d, J=2.2Hz, H-4), 7.20 (2H, m, H-3 ', H-5 '), 7.66 (1H, d, J=
8.7Hz, H-5), 7.70 (1H, m, H-6 '), 8.02 (1H, dq, J=0.6,1.8,8.7Hz, H-6), 8.32 (1H, t, J=
1.8Hz,H-8),10.3(1H,s,HO-3),12.8(1H,s, HO-1)；13C NMR(CD3COCD3,125MHz)δ95.0,
99.2,103.7,105.0,105.2,105.4, 112.8,119.0,126.3,132.8,136.6,156.3,164.7,
166.8,180.9；MS-ESI,m/z 339[M -H]；HRMS(ESI)m/z C19H9F2O4(M-H) calculated value：339.0474, it is real
Measured value：339.0465.
Embodiment 2：6- Trifluoromethyl-1s, the antitumor activity test of 3- dihydroxy xanthones
(1) MTS methods detection cytoactive principle
MTS is a kind of brand-new MTT analogs, and full name is the (3- of 3- (4,5-dimethylthiazol-2-yl) -5
Carboxymethoxyphenyl) -2- (4-sulfopheny) -2H-tetrazolium, it is a kind of dyestuff of yellow color.It is living
Succinate dehydrogenase can be metabolized reduction MTS in cell mitochondrial, generate soluble formazans (Formazan) compound, first
The content of Za can be measured with ELIASA at 490nm., formazan growing amounts and viable count are into just under normal conditions
Than, therefore the number of living cells can be deduced according to optical density OD values.
(2) experimental method
1. inoculating cell：Individual cells are made into the nutrient solution (DMEM or RMPI1640) containing 10% hyclone to hang
Liquid, 96 orifice plates are inoculated into every 3000~15000 cells in hole, per the μ l of pore volume 100, attached cell shifts to an earlier date 12~24h inoculations
Culture.
2. add testing compound solution：Compound is dissolved with DMSO, and compound is whole per hole with 40 μM/L concentration primary dcreening operations
The μ l of volume 200, every kind of processing are all provided with 3 multiple holes.
3. develop the color：After 37 DEG C of culture 48h, attached cell abandons nutrient solution in hole, adds the μ l of MTS solution 20 and nutrient solution per hole
100μl；Suspension cell abandons 100 μ l culture supernatants, and 20 μ l MTS solution is added per hole；If 3 blank multiple holes (μ of MTS solution 20
L and the μ l of nutrient solution 100 mixed liquor), continue 2~4h of incubation, absorbance value is determined after the progress that reacts fully.
4. colorimetric：492nm wavelength is selected, multi-function microplate reader (MULTISKAN FC) reads each hole absorbance value, record
As a result, using compound number as abscissa after data processing, cell inhibitory rate is the inhibiting rate that ordinate draws tumour cell
Figure.
5. 9 kinds of tumour cells of the mankind detected are as follows：Leukemia HL-60, T cell leukaemia MT-4, lung cancer A-549, liver
Cancer SMMC-7721, liver cancer HepG2, liver cancer Huh-7, colon cancer SW 480, breast cancer MCF-7 and s.
6. for tumour cell of the inhibiting rate more than 50%, then determine IC of the compound to the tumour cell50Value.It is real every time
Test and be all provided with two positive compounds of cis-platinum (DDP) and taxol (Taxol), using concentration as abscissa, cell survival rate is sat to be vertical
Plotting cell growth curve, the IC of compound is calculated using two-point method (Reed and Muench methods)50Value.
By MTS methods, with cis-platinum (DDP) and taxol (Taxol) for positive reference compound, a small amount of embodiment 1 is taken to synthesize
7- (2,4- difluorophenyl) -1,3- dihydroxy xanthone (abbreviation chemical compounds I) be dissolved in DMSO, be made into 40 μM/
L solution, inhibitory activity detection (table 1-3) then is carried out to above-mentioned 9 kinds of tumour cells.
Inhibitory activity of the chemical compounds I of table 1 to 5 kinds of tumour cells
Inhibitory activity of the chemical compounds I of table 2 to 4 kinds of tumour cells
IC of the chemical compounds I of table 3 to three kinds of tumour cells50Value
Can be seen that 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthone from table 1-3 has to 9 kinds of tumour cells
The inhibiting rate of inhibitory action, wherein human lung cancer A-549, human liver cancer SMMC-7721 and human T cell leukemia MT-4 cells exceedes
50%, IC50Value is between 18-25 μM, therefore 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthone is to these three mankind
Tumour cell has preferable antitumor activity.
From table 3 it can be seen that IC of 7- (2,4- difluorophenyl) -1, the 3- dihydroxy xanthone to lung cancer A-54950For
24.89 ± 1.11 μM, and cis-platinum is to the IC of lung cancer A-54950For 32.39 ± 0.54 μM, therefore its suppression to lung cancer A-549
Activity is also stronger than cis-platinum.
Embodiment 3：7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthone suppresses the test of tyrosinase activity
7- (2,4- difluorophenyl) -1,3- dihydroxy xanthones are mixed with L-Dopa, it is (dense eventually to add tyrosinase
Degree 25U/mL) start to react, 3 repeating holes are set, while set and be free of 6- Trifluoromethyl-1s, 3- dihydroxy xanthones
Blank control and Kojic Acid positive controls, room temperature, 5min, ELIASA measure OD values, Detection wavelength 490nm.Calculate
To inhibitory activity against tyrosinase.
Inhibitory activity against tyrosinase (%)=(1-sample OD490nm/ experiment contrast hole OD490nm) ×100
Inhibitory action of the chemical compounds I of table 4 to tyrosinase
As can be seen from Table 4：7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthones have suppresses junket to a certain extent
Effect (nearly 20%) of inhibiting rate of propylhomoserin enzyme.
In summary, compound 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthones synthesized by the present invention are new
Xanthone compound, have no that the synthesis and bioactivity of document or patent to it are reported.The compound dialogue blood
Sick HL-60, T cell leukaemia MT-4, lung cancer A-549, liver cancer SMMC-7721, liver cancer HepG2, liver cancer Huh-7, colon cancer SW
480th, breast cancer MCF-7 and 9 kinds of tumour cells of s are all inhibited, wherein to human lung cancer A-549,
3 kinds of tumour cells of human liver cancer SMMC-7721 and human T cell leukemia MT-4 cells all have high inhibition effect, particularly pair
The inhibitory action of lung cancer A-549 is also stronger than clinically wide variety of cis-platinum, can be applied to the production of antineoplastic.
Meanwhile 7- (2,4- difluorophenyl) -1,3- dihydroxy xanthone also suppresses tyrosinase to a certain extent
Effect, therefore it has good transformation or application prospect, can be widely applied to the medicine of tyrosinase Metabolism regulation, protects
Strong product, food.
It should be noted that herein, such as first and second or the like relational terms are used merely to a reality
Body or operation make a distinction with another entity or operation, and not necessarily require or imply between these entities or operation
Any this actual relation or order be present.Moreover, term " comprising ", "comprising" or its any other variant are intended to
Cover including for nonexcludability, so that process, method, article or terminal device including a series of elements are not only wrapped
Those key elements, but also the other element including being not expressly set out are included, or is also included for this process, method, article
Or the key element that terminal device is intrinsic.In the absence of more restrictions, by sentence " including ... " or " including ... "
The key element of restriction, it is not excluded that also exist in addition in the process including the key element, method, article or terminal device
Key element.In addition, herein, " being more than ", " being less than ", " exceeding " etc. are interpreted as not including this number；" more than ", " following ", " with
It is interior " etc. be interpreted as including this number.
Although the various embodiments described above are described, those skilled in the art once know substantially
Creative concept, then other change and modification can be made to these embodiments, so the foregoing is only the implementation of the present invention
Example, not thereby limit the present invention scope of patent protection, every equivalent structure made using present specification or
Equivalent flow conversion, or other related technical areas are directly or indirectly used in, the patent for being similarly included in the present invention is protected
Within the scope of shield.
Claims (10)
1. one kind 2, the xanthone compound of 4- difluorophenyls substitution, it is characterised in that the compound is 7- (2,4- bis-
Fluorophenyl) -1,3- dihydroxy xanthones, shown in its structure such as chemical formula (I)：
2. the preparation method of compound described in a kind of claim 1, it is characterised in that including by 5- (2,4- difluorophenyl) -2-
The process that hydroxybenzoic acid, phloroglucin, phosphorus pentoxide and Loprazolam are reacted.
3. preparation method according to claim 2, it is characterised in that 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids with
The mol ratio of phloroglucin is 1:1.
4. preparation method according to claim 2, it is characterised in that comprise the following steps：
1) phosphorus pentoxide is dissolved in Loprazolam, prepares the first mixed solution；
2) the first mixed solution is added into 5- (2,4- difluorophenyl) -2 hydroxybenzoic acids and phloroglucin, carries out ring-closure reaction,
Generate 7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthones.
5. preparation method according to claim 2, it is characterised in that further comprising the steps of：
The solution containing 7- (2,4 difluorobenzene base) -1,3- dihydroxy xanthones after the completion of the step 2) is reacted is analysed
Go out, filter, column chromatography for separation, 7- (2,4- difluorophenyl) -1, the 3- dihydroxy xanthones purified.
6. preparation method according to claim 4, it is characterised in that in the step 1), solution temperature is controlled 105
~115 DEG C.
7. preparation method according to claim 4, it is characterised in that in the step 2), reaction temperature is controlled 88
~92 DEG C, the reaction time is controlled in 18~22min.
8. the xanthone compound of the 2,4 difluorobenzene base substitution described in claim 1 is in terms of tyrosinase activity is suppressed
Application.
9. xanthone compound the answering in terms of antineoplastic of the 2,4 difluorobenzene base substitution described in claim 1
With.
10. the xanthone compound of the 2,4 difluorobenzene base substitution described in claim 1 is in tyrosinase Metabolism regulation medicine
Application in terms of thing, health products, food, cosmetics.
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| CN108938619A (en) * | 2018-06-29 | 2018-12-07 | 莆田学院 | 7-(2,4- difluorophenyl) the application of -1,3- dihydroxy xanthone in terms of preparing anti-tumor drug |
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| CN108619132B (en) * | 2018-06-29 | 2020-07-17 | 莆田学院 | Application of 7-nitro-1, 3 dihydroxy xanthone in preparation of antitumor drugs |
| CN108689983A (en) * | 2018-07-05 | 2018-10-23 | 莆田学院 | Tri- chloro- 1,3- dihydroxy xanthone compounds of 5,7,8-, preparation method and application |
| CN108689983B (en) * | 2018-07-05 | 2021-09-03 | 莆田学院 | 5,7, 8-trichloro-1, 3-dihydroxy xanthone compound, preparation method and application |
| CN108752306A (en) * | 2018-07-19 | 2018-11-06 | 莆田学院 | Fluoro- 1,3- dihydroxy xanthones of 6- and its preparation method and application |
| CN108997300A (en) * | 2018-07-19 | 2018-12-14 | 莆田学院 | Fluoro- 1,3- dihydroxy xanthone of 7,8- bis- and its preparation method and application |
| CN108997300B (en) * | 2018-07-19 | 2021-09-03 | 莆田学院 | 7, 8-difluoro-1, 3-dihydroxy xanthone and preparation method and application thereof |
| CN108752306B (en) * | 2018-07-19 | 2021-09-17 | 莆田学院 | 6-fluoro-1, 3-dihydroxy xanthone and preparation method and application thereof |
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